Metformin antagonizes nickel-refining fumes-induced cell pyroptosis via Nrf2/GOLPH3 pathway in vitro and in vivo

Zhang, Tong; Wang, Yue; Yao, Wenxue; Chen, Yangyang; Zhang, Dan; Gao, Ying; Jin, Shuo; Li, Lina; Yang, Shikuan; Wu, Yang‐Chang

doi:10.1016/j.ecoenv.2022.114233

Cited by 9 publications

(7 citation statements)

References 63 publications

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“…Therefore, the traceable effect of metformin in inhibiting nickel‐induced ROS is supported. In addition to our previous evidence, metformin also counters nickel‐refined smoke‐induced aerobic glycolysis and cell apoptosis through the ROS/AMPK/GOLPH3 pathway 40,41 …”

Section: Discussionsupporting

confidence: 56%

“…In addition to our previous evidence, metformin also counters nickel-refined smoke-induced aerobic glycolysis and cell apoptosis through the ROS/AMPK/GOLPH3 pathway. 40,41 In addition, evidence has demonstrated that metformin can substantially modulate the processes involved in histone modifications, DNA methylation and miRNAs via the regulation of epigenetic-related gene expression. In our past studies, metformin, in addition to preventing autophagy, can also reduce the expression of oncogenes and reduce the ability to metastasis.…”

Section: Discussionmentioning

confidence: 99%

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Exposure to nickel chloride induces epigenetic modification on detoxification enzyme glutathione S‐transferase M2

Kang,

Yang,

Huang

et al. 2023

Environmental Toxicology

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Nickel (Ni) is a human carcinogen with genotoxic and epigenotoxic effects. Environmental and occupational exposure to Ni increases the risk of cancer and chronic inflammatory diseases. Our previous findings indicate that Ni alters gene expression through epigenetic regulation, specifically impacting E‐cadherin and angiopoietin‐like 4 (ANGPTL4), involved in epithelial‐mesenchymal transition and migration. GST‐M2, a member of the glutathione S‐transferase (GST) enzyme family, plays a crucial role in cellular defense against oxidative damage and has been increasingly associated with cancer. GST‐M2 overexpression inhibits lung cancer invasion and metastasis in vitro and in vivo. Hypermethylation of its promoter in cancer cells reduces gene expression, correlating with poor prognosis in non‐small‐cell lung cancer patients. The impact of Ni on GST‐M2 remains unclear. We will investigate whether nickel exerts regulatory effects on GST‐M2 through epigenetic modifications. Additionally, metformin, an antidiabetic drug, is being studied as a chemopreventive agent against nickel‐induced damage. Our findings indicate that nickel chloride (NiCl2) exposure, both short‐term and long‐term, represses GST‐M2 expression. However, the expression can be restored by demethylation agent 5‐aza‐2′‐deoxycytidine and metformin. NiCl2 promotes hypermethylation of the GST‐M2 promoter, as confirmed by methylation‐specific PCR and bisulfite sequencing. Additionally, NiCl2 also influences histone acetylation, and metformin counteracts the suppressive effect of NiCl2 on histone H3 expression. Metformin reestablishes the binding of specificity protein 1 to the GST‐M2 promoter, which is otherwise disrupted by NiCl2. These findings elucidate the mechanism by which Ni reduces GST‐M2 expression and transcriptional activity, potentially contributing to Ni‐induced lung carcinogenesis.

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Section: Discussionsupporting

confidence: 56%

Section: Discussionmentioning

confidence: 99%

Exposure to nickel chloride induces epigenetic modification on detoxification enzyme glutathione S‐transferase M2

Kang,

Yang,

Huang

et al. 2023

Environmental Toxicology

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“…Mice lacking CREB in the central nervous system show massive apoptosis of postmitotic neurons during development [ 44 ]. Transcriptional cooperation between CREB and Nrf2 enhances resistance to not only apoptosis but also pyroptosis, exerting an anti-inflammatory effect [ 45 , 46 ].…”

Section: Discussionmentioning

confidence: 99%

Protectin conjugates in tissue regeneration 1 alleviates sepsis-induced acute lung injury by inhibiting ferroptosis

Chen

Tian

et al. 2023

J Transl Med

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Background Acute lung injury (ALI) is a common and serious complication of sepsis with high mortality. Ferroptosis, categorized as programmed cell death, contributes to the development of lung injury. Protectin conjugates in tissue regeneration 1 (PCTR1) is an endogenous lipid mediator that exerts protective effects against multiorgan injury. However, the role of PCTR1 in the ferroptosis of sepsis-related ALI remains unknown. Methods A pulmonary epithelial cell line and a mouse model of ALI stimulated with lipopolysaccharide (LPS) were established in vitro and in vivo. Ferroptosis biomarkers, including ferrous (Fe2+), glutathione (GSH), malondialdehyde (MDA) and 4-Hydroxynonenal (4-HNE), were assessed by relevant assay kits. Glutathione peroxidase 4 (GPX4) and prostaglandin-endoperoxide synthase 2 (PTGS2) protein levels were determined by western blotting. Lipid peroxides were examined by fluorescence microscopy and flow cytometry. Cell viability was determined by a CCK-8 assay kit. The ultrastructure of mitochondria was observed with transmission electron microscopy. Morphology and inflammatory cytokine levels predicted the severity of lung injury. Afterward, related inhibitors were used to explore the potential mechanism by which PCTR1 regulates ferroptosis. Results PCTR1 treatment protected mice from LPS-induced lung injury, which was consistent with the effect of the ferroptosis inhibitor ferrostatin-1. PCTR1 treatment decreased Fe2+, PTGS2 and lipid reactive oxygen species (ROS) contents, increased GSH and GPX4 levels and ameliorated mitochondrial ultrastructural injury. Administration of LPS or the ferroptosis agonist RSL3 resulted in reduced cell viability, which was rescued by PCTR1. Mechanistically, inhibition of the PCTR1 receptor lipoxin A4 (ALX), protein kinase A (PKA) and transcription factor cAMP-response element binding protein (CREB) partly decreased PCTR1 upregulated GPX4 expression and a CREB inhibitor blocked the effects ofPCTR1 on ferroptosis inhibition and lung protection. Conclusion This study suggests that PCTR1 suppresses LPS-induced ferroptosis via the ALX/PKA/CREB signaling pathway, which may offer promising therapeutic prospects in sepsis-related ALI.

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“…Mice lacking CREB in the central nervous system show massive apoptosis of postmitotic neurons during development [45]. Transcriptional cooperation between CREB and Nrf2 enhances resistance to not only apoptosis but also pyroptosis, exerting an anti-in ammatory effect [46,47].…”

Section: Pctr1 Suppresses Ferroptosis By Alx/pka/creb Activation In V...mentioning

confidence: 99%

Protectin conjugates in tissue regeneration 1 alleviates sepsis-induced acute lung injury by inhibiting ferroptosis

Chen

Tian

et al. 2023

Preprint

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Background Acute lung injury (ALI) is a common and serious complication of sepsis with high mortality. Ferroptosis, categorized as programmed cell death, contributed to the development of lung injury. Protectin conjugates in tissue regeneration 1 (PCTR1) is an endogenous lipid mediator, exerting protective effects in multi-organ injury. However, the role of PCTR1 in the ferroptosis of sepsis-related ALI remains unknown. Methods Pulmonary epithelial cell line and the mouse model of ALI with lipopolysaccharides (LPS) stimulation were established in vitro and in vivo studies. Ferroptosis biomarkers including Fe2+, GSH, MDA and 4-HNE were detected by relevant assay kits. GPX4 and PTGS2 protein were determined by western blotting. Lipid peroxides were examined by fluorescence microscope and flow cytometry. Cell viability was detected by CCK-8 assay kit. Ultrastructure of mitochondria was observed with transmission electron microscopy. Morphology and inflammatory cytokine level predicted the severity of lung injury. Afterwards, related inhibitors were used to explore the potential mechanism by which PCTR1 regulated ferroptosis. Results PCTR1 treatment protected mice from LPS-induced lung injury, which was consisted with the effect of ferroptosis inhibitor ferrostatin-1. PCTR1 treatment decreased Fe2+, PTGS2 and lipid ROS contents, increased GSH and GPX4 levels and ameliorated mitochondrial ultrastructural injury. Administration of LPS or ferroptosis agonist RSL3 resulted in reduced cell viability, which was rescued by PCTR1. Mechanically, inhibition of PCTR1 receptor ALX, protein kinase A (PKA) and transcription factor cAMP-response element binding protein (CREB) partly decreased PCTR1 up-regulated GPX4 expression and CREB inhibitor blocked the effects of PCTR1 on ferroptosis inhibition and lung protection. Conclusion This study suggests that PCTR1 suppresses LPS-induced ferroptosis via ALX/PKA/CREB signalling pathway, which may offer a promising therapeutic prospect in the sepsis-related ALI.

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Metformin antagonizes nickel-refining fumes-induced cell pyroptosis via Nrf2/GOLPH3 pathway in vitro and in vivo

Cited by 9 publications

References 63 publications

Exposure to nickel chloride induces epigenetic modification on detoxification enzyme glutathione S‐transferase M2

Exposure to nickel chloride induces epigenetic modification on detoxification enzyme glutathione S‐transferase M2

Protectin conjugates in tissue regeneration 1 alleviates sepsis-induced acute lung injury by inhibiting ferroptosis

Protectin conjugates in tissue regeneration 1 alleviates sepsis-induced acute lung injury by inhibiting ferroptosis

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